Pharmaceutical compounds

ABSTRACT

Pyrazole derivatives of the following formula (I), having affinity for the cannabinoidergic CB1 and/or CB2 receptors: 
                         
wherein:
         R is a group selected from
           C 1 -C 10  alkyl;   aryl, arylalkyl or arylalkenyl, not substituted or having from one to four substituents, equal to or different from each other;   
           A is a group selected from the following:
           an ether group of formula —(CH 2 )—O—(CH 2 ) v —R″ wherein
               v is equal to 1 or 2;   R″ is as defined in the present application;   
               a ketone group of formula —C(O)—Z′, wherein Z′ is as defined in the present application;   a substituent having an hydroxyl function of formula —CH(OH)—Z′, being as defined in the present application;   an amide substituent of formula —C(O)—NH-T′, T′ being as defined in the present application;   B is a group as defined in the present application;   
           D is an heteroaryl optionally substituted.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of and claims the benefit under 35U.S.C. §121 of U.S. application Ser. No. 11/134,627, filed May 23, 2005which is hereby incorporated in its entirety by reference. Thisapplication and U.S. application Ser. No. 11/134,627 claim the benefitof Italian Patent Application No. MI 2004 A 001032, filed on May 24,2004, in the Italian Patent and Trademark Office, the disclosure ofwhich is incorporated herein in its entirety by reference.

DETAILED DESCRIPTION

The present invention relates to pyrazole derivatives having affinityfor cannabinoidergic CB1 and/or CB2 receptors, to the correspondingsolvates and pharmaceutically acceptable salts and to theirpharmaceutical compositions.

More specifically the present invention relates to pyrazole derivativescontaining a hetrocyclic ring having affinity for cannabinoidergic CB1and/or CB2 receptors.

Cannabinoids are compounds deriving from sativa Cannabis, commonly knownas marijuana. Among the at least 66 cannabinoid compounds characterizingthe marijuana, tetrahydro-cannabinols (THC) and Δ⁹-tetrahydrocannabinol(Δ⁹-THC) in particular, are considered as the most active. Theproperties which have indeed led to the use of marijuana as therapeuticagent of natural origin in mammalians and in men have been connected tothe above compounds. Said properties, are the following: the analgesiceffect, the antiinflammatory activity, the reduction of the blood andintraocular pressure, the antihemetic activity. The negative effectswhich are associated to the marijuana use have furthermore beencorrelated to tetrahydrocannabinols, with particular reference to thepsychological distortion of the perception, to the motor coordinationloss, to the euphory, to the sedative effect. The cannabinoidpharmacological action appears directly correlated to their affinitytowards two different classes of specific receptors belonging to the “Gprotein-coupled” receptor family: CB1 receptors, located in the centralnervous system besides in the peripheral tissues, and CB2 receptors,identified in the cerebellum (Q. J. Lu et al.; Visual Neurosci.; 2000,17, 9 1-95) but which mainly find in the peripheral tissues (M. Glass;Progr. Neuro-Psychopharmacol. & Biol. Psychiat.; 2001, 25, 743-765). Inthe brain, the CB1 receptors are largely expressed in the hipocampus, inthe cortical regions, in the cerebellum and inside the basal ganglia.Among the peripheral tissues wherein the CB1 receptors have beenlocated, we remember testicles, small intestine, bladder, deferent duct.The CB1 receptors have furthermore been identified in the rat eye and inthe human eye, in the retina and in the iris and in the ciliary body (A.Porcella et al.; Molecular Brain Research; 1998, 58, 240-245; A.Porcella et al.; European Journal of Neuroscience; 2000, 12, 1123-1127).The CB2 receptors are instead mainly located in the marginal spleenzones, in tonsils, besides in several immune system cells, asmacrophages, monocytes, cells of the bone marrow, of thymus andpancreas. Other immune system cells wherein the CB2 receptors aresignificantly present are the T4 and T8 cells, the polymorphonucleateleucocytes, in particular the cells called natural killers andlymphocytes B.

The compounds capable to interact, as agonists or antagonists, with theCB2 receptors can therefore be used in the treatment of diseases whereinimmune system cells or immune disorders are involved. The activation(modulation) of the CB2 receptors is also important in the treatment ofother diseases, as for example in the osteoporosis, renal ischemiatreatment and in inflammatory states.

The compounds with affinity towards the CB1 receptors can be used in thetreatment of eye-diseases as glaucoma, lung-diseases as asthma andchronic bronchitis, inflammations as for example arthritis, allergiesand allergic reactions as for example allergic rhinitis, contactdermatitis, allergic conjunctivitis. Such compounds can also be used inthe pain treatment, in anxiety cases, in mood problems, delirium states,psychotic afflictions in general, besides for schizophrenia, depressiontreatment and when abuse and/or dependency substances are used (forexample alcoholism and tabagism). The same compounds can also be used tocontrast vomit, nausea, giddiness, especially in case of patientssubmitted to chemotherapy; in the treatment of neuropathies, hemicrania,stress, diseases having a psychosomatic origin, epilepsy, Tourettesyndrome, Parkinson disease, Huntington disease, Alzheimer disease,senile dementia, and in case of cognitive disease and memory loss.

Further applications of the compounds having affinity towards CB1receptors are the treatment of pathologies related to the appetite(obesity, bulimia), pathologies of the gastrointestinal tract and of thebladder, cardiovascular diseases, urinary and fertility problems,neuroinflammatory pathologies as for example multiple sclerosis,Guillain-Barré syndrome, viral encephalitis. For example some CB1agonist active principles are successfully used in the nausea and vomittreatment associated to the chemotherapy and in the appetite stimulationin AIDS' patients. Compounds with antagonist activity towards CB1receptors can be used for example in the treatment of psychosis,anxiety, depression, schizophrenia, obesity, neurological diseases (forexample dementia, Parkinson disease, Alzheimer disease, epilepsy,Tourette syndrome), in memory loss, in the pain treatment, in centralnervous system disease involving the neurotransmission of cannabinoids,in the treatment of gastrointestinal and/or cardiovascular troubles.

In connection with the wide pharmacological cannabinoid applications,over the last years several studies have been started to findendocannabinoids and for the synthesis of new compounds capable toselectively interact towards the two subclasses of cannabinoidergic CB1and CB2 receptors. The researches have led on the one hand to theidentification of anandamide endocannabinoids (arachidonyl ethanolamide)and 2-arachidonyl glycerol, on the other hand to the obtainment ofdifferent classes of synthesis compounds, agonists or antagoniststowards the CB1 or CB2 receptors.

The class of the compounds having agonist activity towards the CB1receptors (cannabimimetic activity) comprises synthesis compounds havinga base structure directly derived from that of Δ⁹-THC, as(−)-11-OH-Δ⁸THC-dimethylheptyl (HU210) and nabilone, and compoundsstructurally different from Δ⁹-THC, as aminoalkylindols of the WIN55,212-2 series (M. Pacheco et al.; J. Pharmacol. Exp. Ther.;. 1991,257, 1701-183) or as bicyclic cannabinols (non classic cannabinoids)referring to the compound CP 55,940 (M. Glass; Progr.Neuro-Psychopharmacol. & Biol. Psychiat.; 2001, 25, 743-765). Thecompounds having cannabimimetic activity show in vivo the followingeffects: hypoactivity, hypothermia, analgesia and catalepsy (B. R.Martin et al.; Pharmacol. Biochem. Behav.; 1991, 40, 471-478; P. B.Smith et al.; J. Pharmacol. Exp. Ther.; 1994, 270, 219-227).

Another class of synthesis compounds which have shown themselvesparticularly similar and selective towards cannabinoidergic receptors isthat of the 3-pyrazole carboxylic acid derivatives. The referencecompound of this class of derivatives is commonly indicated with theabbreviation SR141716A:[N-piperidino-5-(4-chlorophenyl)-1-(2,4-dicloro-phenyl)-4-methylpyrazol-3-carboxyamide], described in EP 656,354. In particular theSR141716A compound has shown the following properties: a high affinityfor the CB1 receptors (Ki=1.98±0.36 nM), a significant selectivitytowards the CB1 receptors (affinity towards the CB1 receptors about athousand times higher than that for the CB2 receptors), capability ofinhibiting the cannabinoid activity, therefore antagonist activity, insamples in vivo and in vitro (M. Rinaldi-Carmona et al.; FEBS Lett.;1994, 350, 240-244). On the basis of the properties pointed out, besidesof several clinical and preclinical studies, the SR141716A compound,lately renamed by Sanofi-Synthélabo Rimonabant®, is designed to bemainly used as antihunger active principle in the obesity treatment aswell as in the tabagism treatment.

Patent application US 2001/0053788 describes 4,5-dihydro-1H-pyrazolecompounds as potential antagonists of the CB1 receptors. The generalformula of the claimed compounds is reported hereinafter:

wherein: Q, Q_(a), Q_(b), Q_(c), A_(a), B_(b) have different meanings.

Compounds having high affinity for the cannabinoidergic receptors and,especially, high selectivity for the CB1 receptors, are described in EP1,230,244. In particular, said compounds are tricyclic analogues ofSR141716A having general structure:

wherein Z₁, w₂, w₃, w₄, w₅, w₆, g₂, g₃, g₄, g₅ have different meanings;X—Y— represent a group selected from:—(CH₂)_(r)—CH₂—, —CH₂—S(O)_(p)—, —S(O)_(p)—CH₂—, with r equal to 1 or 2,p equal to zero, 1 or 2. Compounds having high affinity for thecannabinoidergic receptors and, above all, high selectivity for CB2receptors, are described in EP 1,230,222. In particular, the compoundsdescribed in this patent are tricyclic analogues of SR141716A havinggeneral structure:

wherein: -T- represents a —(CH₂)_(m)— group, with m equal to 1 or 2; Z₂,w₂, w₃, w₄, w₅, w₆, g₂, g₃, g₄, g₅ have different meanings.

Other compounds having a pyrazole structure capable to modulate the CB2receptors are described in U.S. Pat. No. 6,100,259 and are representedby the general formula:

wherein q is between 1 and 6, while A_(o), Q_(d), Q_(e), Q_(f), Q_(g)have different meanings.

A further compound having a pyrazole structure with affinity andselectivity towards CB2 receptors is the compound known with theabbreviation SR144528 (M. Rinaldi-Carmona et al. J. Pharmacol. Expt.Ther. 1998 284 644-650) the structure of which is reported hereinafter:

Another compound known for its selectivity towards the CB2 receptors,having agonist activity towards this subclass of receptors, is thecompound 1-propyl-2-methyl-3-naphthoyl-indole, called JWH-015 (M. Glass;Progr. Neuro-Psychopharmacol. & Biol. Psychiat.; 2001, 25, 743-765).

There was still the need of other compounds having affinity for thecannabinoidergic CB1 and/or CB2 receptors.

An object of the present invention are pyrazole derivatives of formula(I), having affinity for the cannabinoidergic CB1 and/or CB2 receptors:

wherein:

-   -   R is a group selected from the following:        -   linear or branched —C₁-C₁₀ alkyl; wherein the end of the            main chain not linked to the nitrogen atom has —CH₂—W            termination, W being a group selected from hydrogen,            halogen, isothiocyanate, CN, OH, OCH₃, NH₂, —CH═CH₂;        -   aryl, arylalkyl or arylalkenyl, not substituted or having            from one to five substituents, equal to or different from            each other, selected from halogen, C₁-C₇ alkyl, C₁-C₇            alkylthio, C₁-C₇ alkoxy, C₁-C₇ haloalkyl, C₁-C₇ haloalkoxy,            cyano, nitro, amino, N-alkylamino, N,N-dialkylamino,            saturated or unsaturated heterocycle, phenyl;    -   A is a group selected from the following:        -   an ether group of formula: —(CH₂)—O—(CH₂)_(v)—R″, wherein:            -   v is an integer equal to 1 or 2;            -   R″ is a saturated or unsaturated heterocycle, or a                C₃-C₁₅ cycloalkyl, or an aryl, or a heteroaryl;        -   a ketonic group of formula —C(O)—Z′, wherein Z′ is as            defined below;        -   a substitutent having an hydroxyl function of formula            —CH(OH)—Z′, Z′ being a C₁-C₈ alkyl or a C₃-C₁₅ cycloalkyl, a            saturated or unsaturated heterocycle, or an aryl, or a            heteroaryl;        -   an amidic substituent of formula —C(O)—NH-T′, T′ being a            group selected from:            -   C₁-C₈ alkyl;            -   C₁-C₇ haloalkyl;            -   aryl, arylalkyl or arylalkenyl, optionally containing                one heteroatom selected among S, N, O, not substituted                or optionally having from one to five substituents, said                substituents equal to or different from each other,                selected from halogen, C₁-C₇ alkyl, C₁-C₇ haloalkyl,                C₁-C₇ haloalkoxy, C₁-C₇ alkylthio, C₁-C₇ alkoxy;            -   a C₃-C₁₅ cycloalkyl not substituted or substituted with                one or more C₁-C₇ alkyl chains, said chains being from                one to four for C₅-C₁₅ cycloalkyls, being from one to                three for the C₄ cycloalkyl, being from one to two for                the C₃ cycloalkyl, said alkyl groups being equal to or                different from each other;            -   a group having formula:

-   -   -   -   wherein R₃ and R₄ equal to or different from each other,                represent hydrogen or C₁-C₃ alkyl, with the proviso that                R₃ and R₄ are not both hydrogen;            -   a group having formula:

-   -   -   -   wherein R₅ represents a C₁-C₃ alkyl and k is an integer                between 1 and 3;

        -   a group NR₁R₂, wherein R₁ and R₂, equal or different, have            the following meanings:            -   hydrogen;            -   C₁-C₇ alkyl;            -   aryl, arylalkyl or arylalkenyl not substituted or                optionally having on the aromatic rings from one to four                substituents, equal to or different from each other,                selected from halogen, C₁-C₇ alkyl, C₁-C₇ haloalkyl,                C₁-C₇ haloalkoxy, C₁-C₇ alkylthio, C₁-C₇ alkoxy, wherein                in the previous substituents comprising C₁-C₇ aliphatic                chains, C₁-C₃ chains are preferably used;

        -   or R₁ and R₂ together with the nitrogen atom to which they            are linked form a, saturated or unsaturated, heterocycle            from 5 to 10 carbon atoms, not substituted or optionally            having from one to four substituents, equal to or different            from each other, selected from C₁-C₇ alkyl, phenyl, benzyl,            said phenyl or benzyl optionally substituted with one or            more groups, equal to or different from each other, selected            from: halogen, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇            haloalkoxy, C₁-C₇ alkylthio, C₁-C₇ alkoxy.

    -   B is a group selected from: halogen; hydrogen; C₁-C₄ alkyl;        C₁-C₆ haloalkyl; C₁-C₆ haloalkoxy; C₁-C₆ alkylthio; C₁-C₆        alkoxy; C₁-C₆ hydroxyalkyl; C₁-C₆ hydroxyalkoxy; cyanomethyl;        C₁-C₆ alkylsulphonyl; C₁-C₆ alkylsulphinyl; —CH₂—NR₆R₇; wherein:

    -   R₆ and R₇, equal to or different, represent each separately:        -   hydrogen;        -   C₁-C₇ alkyl;        -   aryl, arylalkyl or arylalkenyl as defined below, optionally            containing a heteroatom selected from S, N, O, not            substituted or optionally having from one to five            substituents, said substituents equal to or different from            each other, selected from halogen, C₁-C₇ alkyl, C₁-C₇            haloalkyl, C₁-C₇ haloalkoxy, C₁-C₇ alkylthio, C₁-C₇ alkoxy;

    -   or R₆ and R₇ together with the nitrogen atom to which they are        linked form a saturated or unsaturated heterocycle from 5 to 10        carbon atoms, not substituted or optionally having from one to        four substituents, equal to or different from each other,        selected from C₁-C₇ alkyl, phenyl, benzyl, said phenyl or benzyl        optionally substituted with one to five groups, equal to or        different from each other, selected from: halogen, C₁-C₇ alkyl,        C₁-C₇ haloalkyl, haloalkoxy, C₁-C₇ alkylthio, C₁-C₇ alkoxy.

    -   D is an heteroaryl as defined below, optionally substituted with        a number of substituents ranging from 1 to 5 compatibly with the        number of the ring atoms, said substituents equal to or        different from each other, selected from: halogen, C₁-C₇ alkyl,        C₁-C₇ alkylthio, C₁-C₇ alkoxy, C₁-C₇ haloalkyl, C₁-C₇        haloalkoxy, cyano, nitro, amino, N-alkylamino, N,N-dialkylamino,        isothiocyanate, phenyl, cycloalkyl, saturated or unsaturated        heterocycle, heteroaryl.

Where not otherwise specified, in the whole text:

-   -   the term “alkyl” means, a C₁-C₂₀ saturated hydrocarbon chain        linear or branched when possible;    -   the term “alkenyl” means a C₂-C₂₀ mono- or poly-unsaturated,        preferably mono-unsaturated hydrocarbon chain linear or        branched;    -   the term “cycloalkyl” means an aliphatic monocyclic ring, for        example from 3 to 8 carbon atoms, in particular from 4 to 6        carbon atoms, and a polycyclic structure from 8 to 19 carbon        atoms; wherein the ring or the rings do not contain        unsaturations;    -   the term “saturated heterocycle” means a cycloalkyl as above        wherein at least one carbon atom is substituted by one        heteroatom selected from S, O, N; when the ring is monocyclic,        preferably the heteroatoms are no more than 2;    -   the term “unsaturated heterocycle” means a cycloalkyl as above        having one or more double bonds, with the proviso that the        structure does not result of aromatic type, wherein at least one        carbon atom is substituted by one heteroatom selected from S, O,        N;    -   the term “halogen” indifferently indicates an atom selected from        fluorine, chlorine, bromine, iodine;    -   the term “haloalkyl” means an alkyl according to the above        definition, wherein one or more hydrogen atoms are substituted        by as many halogen atoms; for example tri-fluoromethyl,        1-bromo-n-butyl, pentachloroethyl;    -   the term “aryl” means a C₆ monocyclic aromatic radical, or a        C₈-C₁₉ polycyclic radical wherein at least one ring is aromatic,        exclusively containing carbon atoms and hydrogen atoms;    -   the term “heteroaryl” means an aryl as above, except that the        monocyclic radical is C₅-C₆ wherein at least one carbon atom is        substituted by one heteroatom selected from S, O, N; preferably        the heteroatoms in case of monocyclic radicals are no more than        2;    -   the term “arylalkyl” means an alkyl as above, preferably C₁-C₇,        linked to an aryl as above, for example benzyl;    -   the term “arylalkenyl” means an alkenyl as above linked to an        aryl as above;    -   with “compound having affinity towards the receptors” it is        meant a compound which has in vivo agonist, or antagonist, or        partial agonist, or partial antagonist, or opposite agonist, or        opposite antagonist, or opposite partial agonist activity        towards receptors. The meaning of such terms is well known to        the skilled man in the field.

The preferred compounds of formula (I) are those wherein:

-   -   R is a group selected from the following:        -   a linear or branched C₁-C₅ alkyl, wherein the end of the            main chain not linked to the nitrogen atom has —CH₂—W            termination, W being a halogen group;        -   aryl, arylalkyl or arylalkenyl not substituted or containing            from one to five substituents, equal to or different from            each other, selected from halogen, C₁-C₇ alkyl, C₁-C₇            alkylthio, C₁-C₇ alkoxy, C₁-C₇ haloalkyl, C₁-C₇ haloalkoxy,            cyano, nitro, amino, N-alkylamino, N,N-dialkylamino,            saturated or unsaturated heterocycle, phenyl;    -   A is an amide substituent group of formula:        -   —C(O)—NH-T′, wherein T′ has the meanings reported for            formula (I), excluding the formulas (IA) and (IB);    -   B is a group selected from: C₁-C₄ alkyl; C₁-C₆ haloalkyl; C₁-C₆        haloalkoxy; C₁-C₆ alkylthio; C₁-C₆ alkoxy; C₁-C₆ hydroxyalkyl;        C₁-C₆ hydroxyalkoxy; cyanomethyl; —CH₂—NR₆R₇; wherein: R₆ and        R₇, equal to or different, have the meanings indicated above in        formula (I) excluding hydrogen;    -   D is a heteroaryl with ring from 5 to 6 atoms, optionally        substituted with a number of substituents ranging from 1 to 4        for the ring having 5 atoms and from 1 to 5 for the ring having        6 atoms, said substituents equal to or different from each        other, selected from the following: halogen, C₁-C₇ alkyl, C₁-C₇        alkylthio, C₁-C₇ alkoxy, C₁-C₇ haloalkyl, C₁-C₇ haloalkoxy,        cyano, nitro, amino, N-alkylamino, N,N-dialkylamino,        isothiocyanate, phenyl, cycloalkyl, saturated or unsaturated        heterocycle, heteroaryl.

The compounds of formula (I) are still more preferred, wherein:

-   -   R is a group selected from the following:        -   linear or branched C₁-C₆ alkyl, wherein the end of the main            chain not linked to the nitrogen atom has —CH₂—W            termination, W being a halogen group;        -   aryl, arylalkyl or arylalkenyl, not substituted or having            from one to five substituents, equal to or different from            each other, selected from halogen, C₁-C₃ alkyl, C₁-C₃            alkylthio, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy;    -   A is an amide substituent group of formula: —C(O)—NR-T′, wherein        T′ has the following meanings:        -   C₁-C₈ alkyl;        -   C₁-C₇ haloalkyl;        -   aryl, arylalkyl or arylalkenyl, optionally containing one            heteroatom, selected from N, S, O, not substituted or having            from one to five substituents, equal to or different from            each other, said substituents selected from halogen, C₁-C₃            alkyl, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, C₁-C₃ alkylthio,            C₁-C₃ alkoxy;        -   one group NR₁R₂, wherein R₁ and R₂ have the above values in            formula (I);        -   a C₃-C₁₅ cycloalkyl not substituted or substituted with one            or more C₁-C₇ alkyl chains, said chains being from one to            four for C₅-C₁₅ cycloalkyls, being from one to three for the            C₄ cycloalkyl, being from one to two for the C₃ cycloalkyl,            said alkyl groups being equal to or different from each            other;    -   B is a group selected from: C₁-C₃ alkyl; C₁-C₃ haloalkyl; C₁-C₃        haloalkoxy; C₁-C₃ alkylthio; C₁-C₃ alkoxy; C₁-C₃ hydroxyalkyl;        C₁-C₃ hydroxyalkoxy; —CH₂—NR₆R₇; wherein: R₆ and R₇, equal or        different, have the meanings indicated above in formula (I)        excluding hydrogen;    -   D is an heteroaryl selected from the following: thiophene,        pyridine, furan, oxazole, thiazole, imidazole, pyrazole,        isoxazole, isothiazole, triazole, pyridazine, pyrimidine,        pyrazine, triazine, pyrrole; said heteroaryls optionally        substituted with one, two, three or four substituents, equal to        or different from each other, selected from the following:        halogen, C₁-C₃ alkyl, C₁-C₃ alkylthio, C₁-C₃ alkoxy, C₁-C₃        haloalkyl, C₁-C₃ haloalkoxy; preferably the heteroaryls having 5        atoms are used, still more preferably selected between thiophene        and furan.

The compounds of formula (I) are preferably used, wherein A=—C(O)—NH-T′wherein T′ is as above.

Examples of said compounds are the following:

-   N-piperidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   N-homopiperidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   N-pyrrolidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carbohydrazide;-   N-piperidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   N-homopiperidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   N-pyrrolidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carbohydrazide;-   N-piperidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   N-homopiperidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   N-pyrrolidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-methyl-1H-pyrazol-3-carbohydrazide;-   N-piperidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   N-homopiperidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   N-pyrrolidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   p-Diethoxyphenyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carbohydrazide;-   N-piperidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   N-homopiperidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   N-pyrrolidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carbohydrazide;-   N-piperidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   N-homopiperidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   N-pyrrolidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carboxamide;-   p-Methoxyphenyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichloro    phenyl)-4-ethyl-1H-pyrazol-3-carbohydrazide.

The compounds of formula (I) of the present invention depending on thesubstituents can contain one or more chiral centres in their structure.

All the various isomers and the corresponding mixtures are consideredincluded in the present invention. In the compounds of formula (I)cis-trans type isomers can also be present.

The Applicant has surprisingly and unexpectedly found that the compoundsof formula (I) have affinity for the cannabinoidergic CB1 and/or CB2receptors.

The above defined hydrates, solvates and pharmaceutically acceptablesalts of the compounds of formula (I), comprising all the variousisomers and the corresponding mixtures, are a further object of thepresent invention. The meaning of the terms “hydrate” and “solvate” iswell known to the skilled man in the field.

A further object of the present invention is a process for preparing thecompounds of general formula (I) comprising:

-   -   i. synthesis of the acid of the following general formula (II),        or of one of its reactive derivatives, selected from acyl        halides, anhydrides, mixed anhydrides, imidazolides, ester-amide        adducts, linear or branched when possible C₁-C₄ alkyl esters:

-   -   comprising the following steps:        -   obtainment of α-hydroxy-γ-ketoesters of formula (IV),            wherein B and D are as previously defined, starting from a            compound of formula (III) by reaction with an alkaline metal            hydride, for example sodium hydride and diethyloxalate in a            solvent inert under the reaction conditions, for example            DMF, working at room temperature, or anyway between 15° C.            and 30° C. (Claisen condensation):

-   -   -   wherein Me is an alkaline metal;        -   reaction of the compounds of formula (IV) with a hydrazine            of formula (V) wherein R is as previously defined, said            compound (V) optionally being in the form of a hydrochloride            salt, in alcoholic solvent or in acetic acid under reflux,            to obtain the compound of formula (VI), ethyl ester of the            acid of formula (II)

-   -   -   basic hydrolysis with alkaline hydroxides in hydroalcoholic            solution of the compound of formula (VI) under reflux to            obtain the acid of general formula (II);        -   optionally, formation of a reactive derivative of the acid            of general formula (II), said derivative being as defined            above;

    -   ii) when in the general formula (I) A=—(CH₂)—O—(CH₂)_(v)—R″,        wherein R″ is as above, the corresponding compounds can be        prepared starting from the acid of formula (II) or from one of        its esters, for example the ethyl ester, which is reduced in a        first step, by operating at room temperature, into a primary        alcohol in an inert solvent (for example tetrahydrofuran), for        example by using an organic metal hydride, as di-isobutyl        aluminum hydride, or lithium and aluminum hydride; then the        obtained primary alcohol is reacted at room temperature with an        alkyl halide of formula R″—(CH₂)Hal, wherein Hal=halogen, in the        presence of an alkaline hydride, for example sodium hydride, to        obtain the above mentioned compounds, wherein        A=—(CH₂)—O—(CH₂)_(v)—R″.

When in formula (I) A=—C(O)—Z′, Z′ being as above, the compounds offormula (I) can be prepared according to one of the following methods:

-   -   by reacting an ester of the acid of general formula (II),        preferably the ethyl ester with trialkylaluminum, preferably        Al(CH₃)₃ with a hydrochloride salt of an amine, the amine being        a hydrochloride salt preferably HN(OCH₃)CH₃.HCl in a solvent        inert under the reaction conditions, preferably dichloromethane,        initially at 0° C., then at room temperature until the ester        disappearance; then by adding at 0° C. to the reaction mixture        Z′MgBr, wherein Z′ is as above, and allowing to react at room        temperature until obtaining the compound of formula (I) wherein        R′═—C(O)—Z′;    -   by reacting the acid of formula (II), or one of its reactive        derivatives, with an organic metal salt of formula Z′⁻ Me⁺        wherein Me⁺ is preferably an alkaline metal cation for example        lithium, in a solvent inert under the reaction conditions,        obtaining the compound of formula (I) wherein R′═—C(O)—Z′.

The former of the two above processes is preferably used.

When in the general formula (I) A=—CH(OH)—Z′, wherein Z′ is as above,the synthesis is carried out in two steps:

-   -   preparation of the compound of formula (I) wherein R′═—C(O)—Z′        by using one of the two reactions reported above;    -   reaction of the compound of formula (I) wherein R′═—C(O)—Z′ with        lithium and aluminum hydride or sodium borohydride at room        temperature to give the final product of formula (I) wherein        A=—CH(OH)—Z′.

When in the general formula (I) A=—C(O)—NH-T′, wherein T′ is as above,the compounds are prepared by reaction in a solvent inert under thereaction conditions of the acid of formula (II) in the form of acorresponding reactive derivative as above, generally at roomtemperature with a compound of general formula:H₂N-T′  (VII)wherein T′ has the previously defined meanings.

The compounds of formula (III) and (VII) are available on the market orare described in the publications of the field.

Preferred examples of acids of formula (II) are the following:

-   5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-thiophen-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-thiophen-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-thiophen-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-thiophen-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-thiophen-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-thiophen-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-furan-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-furan-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-furan-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-furan-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-furan-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-furan-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-furan-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-furan-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-furan-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-furan-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-furan-2-yl)-1-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-furan-2-yl)-1-(4-methoxy-phenyl)-4-methyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-thiophen-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-thiophen-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-thiophen-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-thiophen-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-thiophen-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-thiophen-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-thiophen-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-furan-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Chloro-furan-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-furan-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Bromo-furan-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-furan-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(5-Methyl-furan-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-furan-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Chloro-furan-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-furan-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Bromo-furan-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-furan-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-furan-2-yl)-1-(4-chloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid;-   5-(4-Methyl-furan-2-yl)-1-(4-methoxy-phenyl)-4-ethyl-1H-pyrazol-3-carboxylic    acid.

With pharmaceutically acceptable salts all the salts are meant obtainedby treating the compounds of formula (I) with organic or inorganic acidsacceptable from the pharmaceutical point of view. For examplehydrochlorides, sulphates, fumarates, oxalates, citrates,hydrogensalphates, succinates, paratoluensulphonates can be mentioned.See the publication: “Remington, The Science and Practice of Pharmacy”,vol. II, 1995, page 1457.

A further object of the present invention is represented by thepharmaceutical compositions containing the compounds of general formula(I), comprising the isomers and their mixtures, the correspondinghydrates or solvates or pharmaceutically acceptable salts.

With pharmaceutical compositions, preparations are meant wherein theactive principles of formula (I), comprising all the different isomersand the corresponding mixtures, or the corresponding hydrates orsolvates or pharmaceutically acceptable salts, are mixed withexcipients, carriers, dyes, preservatives, flavorings and otheradditives the use of which is known in the pharmaceutical field.

The pharmaceutical compositions of the present invention can beadministered by os, subcutaneous, sublingual, intramuscular,intravenous, topical, transdermal, rectal, ophtalmic, intranasal route.Said pharmaceutical compositions comprise for example dispersions,solutions, emulsions, microemulsions, powders, capsules, aerosol,suppositories, tablets, syrups, elixir, creams, gels, ointments,plasters.

The pharmaceutical compositions of the present invention can be obtainedaccording to known methods of the pharmaceutical technique. For example,said pharmaceutical compositions can be obtained according to theprocesses indicated in U.S. Pat. No. 6,028,084, herein incorporated byreference.

The pharmaceutical compositions can also be prepared by using themethods and the additives indicated in patent applicationUS2003/0003145. In these formulations sodium alkylsulphate or anothersurfactant commonly utilized in the pharmaceutical field can be used.

For example pharmaceutical compositions, usable for the oraladministration of the compounds of formula (I) or of the correspondinghydrates or solvates or pharmaceutically acceptable salts, are formedof: 0.5-20% by weight of a compound of formula (I), comprising all thevarious isomers and the corresponding mixtures or of a correspondinghydrate or solvate or pharmaceutically acceptable salt; 0.05-0.5% byweight of sodium alkylsulphate or another surfactant; 2.5-10% by weightof a disgregating agent as for example cellulose, sodiumcarboxymethylcellulose or other cellulose derivatives.

The compounds of formula (I), including the various isomers and relatedmixtures, and the corresponding hydrates or solvates andpharmaceutically acceptable salts and their pharmaceutical compositionsof the present invention have a high affinity in vitro for thecannabinoidergic CB1 and/or CB2 receptors. See the Examples. Morespecifically the compounds of the present invention have a Ki value forthe CB1 and/or CB2 receptors lower than 0.5 μM.

The present invention also relates to the use of compounds of formula(I), including the various isomers and the respective mixtures, thecorresponding hydrates or solvates or pharmaceutically acceptable salts,or the pharmaceutical compositions containing them, for preparingproducts for the treatment in mammalians and in men of diseases whereinthe CB1 and/or CB2 receptors are involved.

In particular the compounds of formula (I) comprising the variousisomers and respective mixtures, or the corresponding hydrates orsolvates or pharmaceutically acceptable salts, or in the form of thecorresponding pharmaceutical compositions, having affinity towards theCB2 receptors, can therefore be used in the treatment of diseases inwhich immune system cells or immune disorders are involved, or in thetreatment of other pathologies, as for example osteoporosis, renalischemia and in case of inflammatory states.

The compounds of the present invention, including the various isomersand respective mixtures, and the corresponding hydrates or solvates andpharmaceutically acceptable salts and the respective pharmaceuticalcompositions, having affinity towards the CB2 receptors, can also beused in case of diseases related to organ transplants and preventiverejection therapies in the allogenic transplant, in the transplantrejection treatment also in patients which have received otherimmunosuppressive therapies, in the treatment and prophylaxis of GVHD(Graft Versus Host Disease), in the treatment of diseases as:erythematous systemic lupus, ankylosing spondylitis, polyarthritisrheumatoid, hemolytic autoimmune anemia, Behcet disease, Sjögrensyndrome, undifferentiated spondylarthritis, reactive arthritis,dermatomyositis.

Furthermore the compounds of formula (I) comprising the various isomersand respective mixtures or the corresponding hydrates or solvates orpharmaceutically acceptable salts, or in the form of the correspondingpharmaceutical compositions, having affinity towards the CB1 receptors,can be used in the treatment of ocular diseases, as glaucoma or ocularhypertonia, lung-diseases as asthma and chronic bronchitis, allergiesand allergic reactions (for example allergic rhinitis, contactdermatitis, allergic conjunctivitis), inflammations as for examplearthritis.

The compounds of formula (I) comprising the various isomers andrespective mixtures and the corresponding hydrates or solvates andpharmaceutically acceptable salts and the respective pharmaceuticalcompositions, having affinity towards the CB1 receptors, can also beused as analgesics in the pain treatment, in cases of anxiety, of moodproblems, delirium states, psychotic afflictions in general, for theschizophrenia, depression treatment, when abuse and/or addictionsubstances are used (for example alcoholism and tabagism).

The compounds of formula (I) comprising the various isomers andrespective mixtures and the corresponding hydrates or solvates andpharmaceutically acceptable salts and the respective pharmaceuticalcompositions, having affinity towards the CB1 receptors, can also beused to contrast vomit, nausea, giddiness, especially in case ofpatients subjected to chemotherapy, in the treatment of neuropathies,hemicrania, stress, diseases having a psychosomatic origin, epilepsy,Tourette syndrome, Parkinson disease, Huntington disease, Alzheimerdisease, senile dementia, in case of cognitive disease and memory loss,in the treatment of problems connected to appetite (obesity, bulimia),in the treatment of pathologies of the gastrointestinal tract and of thebladder, of cardiovascular diseases, in case of urinary and fertilityproblems, in the treatment of neuroinflammatory pathologies as forexample multiple sclerosis, Guillain-Barré syndrome, viral encephalitis.

Among the compounds object of the present invention, comprising thevarious isomers and respective mixtures and the corresponding hydratesor solvates and pharmaceutically acceptable salts and theirpharmaceutical compositions, those having affinity towards the CB1receptors at least five times, preferably at least ten times higher thanthat for the CB2 receptors, are preferably used for the treatment ofdiseases wherein the CB1 receptors are involved.

The compounds of formula (I) comprising the isomers and thecorresponding mixtures, the corresponding hydrates or solvates orpharmaceutically acceptable salts, or in the form of the correspondingpharmaceutical compositions, having an affinity towards the CB2receptors at least five times, preferably at least ten times higher thanthat for the CB1 receptors, are instead preferably used for thetreatment of diseases wherein the CB2 receptors are involved.

The use of the compounds of formula (I) comprising the various isomersand their mixtures, and the corresponding hydrates or solvates andpharmaceutically acceptable salts, and the respective pharmaceuticalcompositions, for the treatment of the different pathologies wherein themodulation of the CB1 and/or CB2 receptors is involved as above, can bemade by utilizing the known methods used for said treatments.

In particular the administration of the compounds must be carried out ina sufficiently effective amount for the specific treatment. Analogouslythe dosages, the administration route and the posology will beestablished depending on the disease typology, on the pathologyseriousness, on the physical conditions and characteristics of thepatient (for example age, weight, response to the active principle), onthe pharmacokinetics and toxicology of the compounds of formula (I)selected for the specific treatment.

The preferred daily dosage interval is 0.01-100 mg of compound offormula (I) of the invention per Kg of body weight of mammalian to betreated. In men, the preferred daily dosage interval is 0-1000 mg ofcompound per Kg of body weight, still more preferred from 1 to 200 mg.

A further object of the present invention is the use of compounds offormula (I), comprising the isomers and the corresponding mixtures, orof the corresponding hydrates or solvates or pharmaceutically acceptablesalts, radiomarked, and of the respective pharmaceutical formulations,for the identification and marking of the cannabinoidergic CB1 or CB2receptors in mammalians or in men.

Furthermore the compounds of formula (I) containing a hydroxyl group,comprising the isomers and the corresponding mixtures, or thecorresponding hydrates or solvates or pharmaceutically acceptable salts,and the respective pharmaceutical formulations, can be used to obtainligands, possibly detectable by immunochemical methods, to be used inthe isolation, purification and characterization of the CB1 or CB2receptors and in the identification of the corresponding active sites.

The following Examples are given to better understand the presentinvention and are not anyway limitative thereof.

EXAMPLES Example 1.1 Preparation of the ethyl ester of the5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylicacid

1.1a) Preparation of ethyl4-(5-chloro-thiophen-2-yl)-3-methyl-2,4-dioxy-butyrate

To a solution of 5-chloro-2-propionyl-thiophene (5.72 mmol, 1 eq) indimethylformamide (10 ml) sodium hydride is added in dispersion inmineral oil at 60% by weight (6.87 moles, 1.2 eq) at a temperature ofabout 10° C. It is left under stirring at the indicated temperature forfurther 10 minutes. Lastly diethyloxalate (6.87 mmol, 1.2 eq) is added.The reaction mixture is stirred at room temperature for 3 hours, thenpoured in H₂O/ice and acidified with HCl 1N. The aqueous solution isrecovered and extracted with AcOEt. The organic phase is washed withwater, then dried on Na₂SO₄ and the solvent removed by evaporation underreduced pressure. The obtained raw product is purified by flashchromatography (oil ether/ethyl acetate 8/2 v/v on silica gel). Thediketoester is isolated under the form of a yellow oil (1.37, yield28.18%) in admixture with the starting product. Analyticalcharacteristics of the diketoester: Rf 0.392 (oil ether/ethyl acetate8/2 on silica gel plates); m.p. 25-26° C.; IR (nujol) (λ=cm⁻¹) 1653(C═O); 1731 (C═O); 1751 (C═O); ¹H-NMR (CDCl₃) δ 1.31 (t, 3H; J=7.0 Hz);1.48 (d, 3H, J=7.2 Hz); 4.29 (q, 2H, J=7.0 Hz); 4.79 (q, 1H, J=7.2 Hz);7.02 (d, 1H, J=4.2 Hz); 7.60 (d, 1H, J=4.2 Hz); Anal. calc. forC₁₁H₁₁ClO₄S: C, 48.09; H, 4.04; Cl, 12.90. Found: C, 48.23; H, 4.13; Cl,12.98.

1.1b) Synthesis of the ethyl ester of the5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylicacid

A mixture formed of the compound obtained in the previous reaction (3.64mmol, 1 eq) and 2.4-dichlorophenyl-hydrazine hydrochloride (4.00 mmol,1.1 eq) in acetic acid (2 ml), was reacted at the reflux temperature for1.5 hours. Then the mixture was cooled at room temperature, poured inwater and the pH neutralized by adding a NaHCO₃ solution. The aqueousphase is then extracted with ethyl ether, the ether phase washed with asaturated NaHCO₃ solution, dried over Na₂SO₄ and concentrated byremoving the solvent. A raw product was obtained which is purified byflash chromatography (oil ether/ethyl acetate 8/2 v/v) lastly isolatingthe ester in the form of a red-orange oil which tends to solidify (0.83g, yield 54.97%). Rf 0.537 (oil ether/ethyl acetate 8/2, silica gelplates); m.p.: 91-92° C.; IR (nujol) (λ=cm⁻¹) 1710 (C═O); ¹H-NMR (CDCl₃)δ 1.42 (t, 3H, J=7.0 Hz); 2.42 (s, 3R); 4.44 (q, 2H, J=7.0 Hz); 6.67 (d,1H, J=4.0 Hz); 6.82 (d, 1H, J=4.0 Hz); 7.34-7.36 (m, 2H); 7.46-7.47 (m,1H); Anal. calc. for C₁₇H₁₃Cl₃N₂O₂S: C, 49.12; H, 3.15; Cl, 25.58; N,6.74. Found: C, 49.54; H, 3.18; Cl, 25.76; N, 6.88.

Example 1.2 Preparation of the ethyl ester of the5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylicacid 1.2a) Ethyl 4-(5-chloro-thiophen-2-yl)-3-ethyl-2,4-dioxy-butyrate

To a solution of 5-chloro-2-butyryl-thiophene (5.72 mmol, 1 eq) indimethylformamide (10 ml) sodium hydride was added in dispersion withmineral oil at 60% (6.87 moles, 1.2 eq) at a temperature of about 10° C.It is left under stirring at this temperature for further 10 min. Lastlydiethyloxalate (6.87 moles, 1.2 eq) is added and it is reacted, understirring, at room temperature for 3 hours. At the end the reactionmixture is poured in H₂O/ice and acidified with HCl 1N. The aqueoussolution is then extracted with AcOEt, the organic phase recovered,washed with H₂O, dried over Na₂SO₄ and the solvent evaporated underreduced pressure. A raw product is obtained which is purified by flashchromatography (oil ether/ethyl acetate 8/2) to give a mixture of ayellow oil diketoester (0.26 g, yield 15.8%) together with the startingproduct. Analytical characteristics of the diketoester: Rf 0.459 (oilether/ethyl acetate 8/2); m.p. 28-29° C.; IR (nujol) (λ=cm⁻¹) 1652(C═O); 1730 (C═O); 1773 (C═O); ¹H-NMR (CDCl₃) δ 0.99 (t, 3H, J=7.6 Hz);1.31 (t, 3H, J=7.0 Hz); 1.91-2.16 (m, 2H); 4.28 (q, 2H, J=7.2 Hz); 4.70(t, 1H, J=6.8 Hz); 7.02 (d, 1H, J=4.2 Hz); 7.61 (d, 1H, J=4.2 Hz); Anal.calc. for C₁₂H₁₄ClO₄S: C, 50.03; H, 4.55; Cl, 12.24. Found: C, 49.91; H,4.54; Cl, 12.28.

1.2b) Preparation of the ethyl ester of the5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylicacid

A mixture formed of the compound isolated in the previous step (1.73mmoles, 1 eq) and 2,4-dichlorophenyl-hydrazine hydrochloride (1.90 mmol,1.1 eq) in acetic acid (2 ml), was reacted at the reflux temperature for1.5 hours and then cooled at room temperature. The reaction mixture waspoured in H₂O, neutralized with NaHCO₃, then extracted with ethyl ether.The ether phase was washed with a saturated NaHCO₃ solution, dried overNa₂SO₄, and the solvent removed under reduced pressure. A raw product isobtained from which by flash chromatography (oil ether/ethyl acetate8/2) the ester is isolated in the form of a white-orange solid (0.50 g,yield 67.23%). Rf 0.609 (oil ether/etyl acetate 8/2); m.p.: 91-92° C.;IR (nujol) (λ=cm⁻¹) 1712 (C═O); ¹H-NMR (CDCl₃) δ 1.23 (t, 3H, J=7.6 Hz);1.42 (t, 3H, J=7.0 Hz); 2.84 (q, 2H, J=7.4 Hz); 4.45 (q, 2H, J=7.4 Hz);6.57 (d, 1H, J=3.6 Hz); 6.81 (d, 1H, J=3.8 Hz); 7.34-7.36 (m, 2H);7.46-7.47 (m, 1H); Anal. calc. for C₁₉H₁₅Cl₃N₂O₂S: C, 50.37; H, 3.53;Cl, 24.68; N, 6.50. Found: C, 50.31; H, 3.52; Cl, 24.75; N, 6.52.

Example 1.3 Preparation of the ethyl ester of the1-(5-Chloropentyl)-5-(5′-chloro-thiophen-2′-yl)-4-methyl-1H-pyrazol-3-carboxylicacid

The same method reported in the Example 1.2b was used to react thediketoester prepared in the Example 1.1a with chloropentyl hydrazine toform the pyrazol-ester compound. The purification by flashchromatography (oil ether/ethyl acetate 8/2), has given (yield 15%) anorange-coloured oil. Rf=0.23 (oil ether/ethyl acetate 8/2); m.p.: 63-64°C./2.7 mm Hg; IR (nujol) (λ=cm⁻¹) 1716 (COOEt); ¹H-NMR (CDCl3) δ1.34-1.44 (m, 5H); 1.66-1.88 (m, 4H); 2.23 (s, 3H); 3.48 (t, 2H, J=6.4Hz); 4.15 (t, 2H, J=7.4 Hz); 4.42 (q, 2H, J=7.2 Hz); 6.85 (d, 1H, J=3.8Hz); 7.00 (d, 1H, J=3.8 Hz); Anal. calc. for Cl₆H₂₀Cl₂N₂O₂S: C, 51.20;H, 5.37; Cl, 18.89; N, 7.46; S, 8.54. Found: C, 51.12; H, 5.37; Cl,18.92; N, 7.49; S, 8.55.

Example 2.1 Preparation of the5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylicacid

To a solution in methanol (9 ml) of the ester (2 mmol, 1 eq) obtained inthe Example 1.1, a methanol solution (7 ml) of KOH (4 mmol, 2 eq) wasadded. It is left under stirring under reflux for 8 hours. The reactionmixture is then poured in water and ice and acidified with HCl 1N. Theprecipitate which forms is filtered under vacuum. The solid is thenwashed with H₂O and dried in a stove obtaining 0.67 g (yield 86.45%) ofthe expected acid as an analytically pure white solid. Rf 0.472(chloroform/methanol 9/1); m.p.: 215-216° C.; IR (nujol) (λ=cm⁻¹) 1686(C═O); ¹H-NMR (CDCl₃) δ 2.44 (s, 3H); 6.69 (d, 1H, J=3.6 Hz); 6.83 (s,1H, J=3.6 Hz); 7.34-7.40 (m, 3H, OH exchanges with D₂O); 7.44-7.50 (m,1H); Anal. calc. for C₁₅H₉Cl₃N₂O₂S: C, 46.47; H, 2.34; Cl, 27.44; N,7.23. Found: C, 46.54; H, 2.19; Cl, 27.28; N, 7.06.

Example 2.2 Preparation1-(5-Chloropentyl)-5-(5′-chloro-thiophen-2′-yl)-4-methyl-1H-pyrazol-3-carboxylicacid

To a solution of the tricyclic ester prepared in the Example 1.2c (2.00mmol, 1 eq) in methanol (10 ml), KOH (4 mmol, 2 eq) solubilized inmethanol (7 ml) was added. The reaction mixture was stirred under refluxfor 8 hours. Then it was poured in water and ice and acidified with HCl1N. The solution was extracted with ethyl ether. The organic phase wasanhydrified over Na₂SO₄ and then the solvent was removed under reducedpressure. The expected acid was thus obtained (yield 90%) asorange-coloured oil. Rf=0.47 (chloro-form/methanol 9/1); b.p.: 94-95°C./2.7 mm Hg; IR 1693 (C═O); ¹H-NMR (CDCl₃) δ 1.37-1.48 (m, 2H);1.64-1.88 (m, 4H); 2.26 (s, 3H); 3.50 (t, 2H, J=6.6 Hz); 4.15 (t, 2H,J=7.2 Hz); 6.87 (d, 1H, J=4.0 Hz); 7.01 (d, 1H, J=4.0 Hz); Anal. calc.for C₁₄H₁₆Cl₂N₂O₂S: C, 48.42; H, 4.64; Cl, 20.42; N, 8.07; S, 9.23.Found: C, 48.31; H, 4.63; Cl, 20.45; N, 8.09; S, 8.25.

Esempio 2.3 Preparation of the5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-carboxylicacid

To a solution in methanol (5.5 ml) of the ester prepared in the Example1.2 (1.16 mmol, 1 eq), a KOH solution (2.23 mmol, 2 eq) in methanol (4ml) was added. The reaction mixture was maintained under reflux understirring overnight. At the end it is poured in water and ice andacidified with HCl 1N. The precipitate is filtered under vacuum, washedwith H₂O and dried in a stove obtaining 0.40 g (yield 85.84%) of theacid in the form of an analytically pure white solid. Rf 0.428(chloroform/methanol 9/1); m.p.: 207-208° C.; IR (nujol) (λ=cm⁻¹) 1692(C═O); 3434 (OH); ¹H-NMR (CDCl₃) δ ¹H-NMR (CDCl₃): 1.25 (t, 3H, J=7.4Hz); 2.85 (q, 2H, J=7.4 Hz); 4.81 (br s, 1H, OH exchanges with D₂O);6.67 (d, 1H, J=4.0 Hz); 6.82 (d, 1H, J=4.0 Hz); 7.31-7.40 (m, 2H); 7.49(s, 1H); Anal. calc. for C₁₆H₁₁Cl₃N₂O₂S: C, 47.93; H, 2.77; Cl, 26.41;N, 6.99. Found: C, 47.84; H, 2.76; Cl, 26.48; N, 6.97.

Example 3.1a Preparation of the ester-amide adduct of the5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylicacid

To a suspension of the acid obtained in the Example 2.1 (0.64 mmol, 1eq) in dichloromethane (1.3 ml), HOBt (1-hydroxybenzotriazole, 0.77mmol, 1.2 eq) and EDC (1-(3-diamino propyl)-3-ethylcarbodiimidehydrochloride, 0.77 mmol, 1.2 eq) were added. The solution wasmaintained under stirring at room temperature for 30 min, then used assuch to prepare the compounds described hereinafter in the Examples3.1b-3.1g, without isolating the amide which was formed.

Example 3.1b Preparation ofN-piperidinyl-5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxamide

The solution containing the ester-amide adduct prepared in the Example3.1a was added, by quick dripping, to a solution of 1-aminopiperidine(1.28 mmol, 2 eq) in dichloromethane (2 ml). The reaction mixture wasstirred at room temperature for 30 min.

After having removed the solvent, the obtained product was treated withoil ether and purified by flash chromatography (oil ether/ethyl acetate8/2) obtaining 0.16 g (yield 55.17%) of carboxamide in the form of awhite solid. Rf 0.25 (oil ether/ethyl acetate 8/2); m.p.: 125-126° C.;IR (nujol) (λ=cm⁻¹) 1662 (C═O); 3213 (NH); ¹H-NMR (CDCl₃) δ 1.38-1.50(m, 2H); 1.69-1.80 (m, 4H); 2.45 (s, 3H); 2.85 (t, 4H, J=5.6 Hz); 6.65(d, 1H, J=4.0 Hz); 6.81 (d, 1H, J=4.0 Hz); 7.30-7.36 (m, 2H; NHexchanges with D₂O); 7.49-7.51 (m, 1H); 7.61 (s, 1H); ¹³C-NMR (CDCl₃) δ9.56 (CH₃); 23.33 (CH₂); 25.40 (2×CH₂); 57.08 (2×CH₂); 119.44 (C);126.39 (CH); 127.79 (C); 127.97 (CH); 128.17 (CH); 130.22 (C); 130.32(CH); 130.75 (CH); 130.84 (C); 133.73 (C); 135.62 (C); 136.54 (C);144.28 (C) 159.70 (CO); Anal. calc, for C₂₀H₁₉Cl₃N₄OS: C, 51.13; H,4.08; Cl, 22.64; N, 11.93. Found: C, 51.24; H, 4.09; Cl, 22.58; N,11.90.

Example 3.1c Preparation ofN-homopiperidinyl-5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxamide

The solution containing the ester-amide adduct prepared in the Example3.1a was added, by quick dripping, to a solution of1-amino-homo-piperidine (1.28 mmol, 2 eq) in dichloromethane (2 ml). Thereaction mixture was stirred at room temperature for 30 min. Afterhaving removed the solvent, the obtained product was treated with oilether and purified by flash chromatography (oil ether/ethyl acetate 8/2)obtaining 0.10 g (yield 32.26%) of carboxamide in the form of a whitesolid. Rf 0.375 (oil ether/ethyl acetate 8/2); m.p.: 134-135° C.; IR(nujol) (λ=cm⁻¹) 1660 (C═O); 3289 (NH); ¹H-NMR (CDCl₃) δ 1.60-1.80 (m,8H); 2.46 (s, 311); 3.14 (t, 4H, J=5.8 Hz); 6.65 (d, 1H, J=4.0 Hz); 6.81(d, 1H, J=4.0 Hz); 7.32-7.35 (m, 2H); 7.49-7.51 (m, 1H); 8.02 (br s, 1H,NH exchanges with D₂O); ¹³C-NMR (CDCl₃) δ 9.56 (CH₃); 26.30 (2×CH₂);26.94 (2×CH₂); 58.33 (2×CH₂); 119.31 (C); 126.37 (CH); 127.32 (C);127.94 (CH); 128.13 (CH); 130.29 (CH); 130.72 (CH); 132.41 (C); 132.71(C); 135.62 (C); 136.48 (C); 136.89 (C) 144.23 (C) 160.02 (CO); Anal.calc. for C₂₁H₂₁Cl₃N₄OS: C, 52.13; H, 4.37; Cl, 21.98; N, 11.58. Found:C, 52.04; H, 4.35; Cl, 22.02; N, 11.61.

Example 3.1d Preparation ofN-pyrrolidinyl-5-(5-Chloro-thiophen-2-yl)-1-(2,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxamide

The solution containing the ester-amide adduct prepared in the Example3.1a was added, by quick dripping, to a solution of 1-aminopyrrolidinehydrochloride (1.28 mmol, 2 eq) and TEA (1.28 mmol, 2 eq) indichloromethane (2 ml). The reaction mixture was stirred at roomtemperature for 30 min. After having removed the solvent, the obtainedproduct was treated with oil ether and purified by flash chromatography(oil ether/ethyl acetate 7/3) obtaining 0.37 g (yield 77.42%) ofcarboxamide as a white solid. Rf 0.178 (oil ether/ethyl acetate 7/3);m.p.: 187-188° C.; IR (nujol) (λ=cm⁻¹) 1664 (C═O); 3215 (NH); ¹H-NMR(CDCl₃) δ 1.82-1.95 (m, 4H); 2.46 (s, 3H); 2.94-3.05 (m, 4H); 6.65 (d,1H, J=3.8 Hz); 6.81 (d, 1H, J=3.8 Hz); 7.33-7.36 (m, 2H); 7.49-7.51 (m,1H); 7.58 (br s, 1H, NH exchanges with D₂O); ¹³C-NMR (CDCl₃) δ 9.57(CH₃); 22.21 (2×CH₂); 54.41 (2×CH₂); 119.32 (C); 126.38 (CH); 127.27(C); 127.96 (CH); 128.15 (CH); 130.31 (CH); 130.72 (CH); 132.44 (C);133.73 (C); 135.59 (C); 136.54 (C); 136.96 (C) 144.22 (C) 160.57 (CO);Anal. calc. for C₁₉H₁₇Cl₃N₄O₆: C, 50.07; H, 3.76; Cl, 23.03; N, 12.29.Found: C, 50.12; H, 3.77; Cl, 23.27; N, 12.31.

Example 3.1e Preparation ofN-phenyl-5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxamide

The solution containing the ester-amide adduct prepared in the Example3.1a was added, by quick dripping, to an aniline solution (1.28 mmol, 2eq) in dichloromethane (2 ml). The reaction mixture was stirred at roomtemperature for 1 h. After having removed the solvent, the obtainedproduct was treated with oil ether and purified by flash chromatography(oil ether/ethyl acetate 8/2) obtaining 0.33 g (yield 56.67%) ofcarboxamide in the form of a solid. Rf 0.661 (oil ether/ethyl acetate8/2); m.p. 175-176° C.; IR (nujol) (λ=cm⁻¹) 1676 (C═O); 3378 (NH);¹H-NMR (CDCl₃) δ 2.52 (s, 3H); 6.69 (d, 1H, J=3.8 Hz); 6.83 (d, 1H,J=3.8 Hz); 7.11 (t, 1H, J=7.4 Hz); 7.31-7.43 (m, 4H); 7.53 (s, 1H); 7.67(d, 2H, J=7.8 Hz); 8.74 (br s, 1H, NH exchanges with D₂O); ¹³C-NMR(CDCl₃) δ 9.72 (CH₃); 119.45 (C); 119.72 (CH x2); 124.07 (CH); 126.44(CH); 127.10 (C); 128.01 (CH); 128.36 (CH); 128.97 (CH x2); 130.36 (CH);130.69 (CH); 132.63 (C); 133.76 (C); 135.53 (C); 136.67 (C); 137.48 (C);137.76 (C); 144.74 (C); 160.24 (CO); Anal. calc. for C₂₁H₁₄Cl₃N₃OS: C,54.50; H, 3.05; Cl, 22.98; N, 9.08; S, 6.93. Found: C, 54.36; H, 2.98;Cl, 22.79; N, 8.95; S, 6.87.

Example 3.1f Preparation ofN-phenyl-5-(5-Chloro-thiophen-2-yl)-1-(2′,4′-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carbohydrazide

The solution containing the ester-amide adduct prepared in the Example3.1a was added, by quick dripping, to a solution of phenylhydrazinehydrochloride (1.28 mmol, 2 eq) and TEA (1.28 mmol, 2 eq) indichloromethane (2 ml). The reaction mixture was stirred at roomtemperature for 30 min. After having removed the solvent, the obtainedproduct was treated with oil ether and purified by flash chromatography(oil ether/ethyl acetate 8/2) obtaining 0.38 g (yield 62.10%) of theexpected product as a yellow solid. Rf 0.321 (oil ether/ethyl acetate8/2); m.p.: 154-155° C.; IR (nujol) (λ=cm⁻¹) 3302 (NH); 3187 (NH); 1680(CO); ¹H-NMR (CDCl₃) δ 2.44 (s, 3H); 6.18 (d, 1H, NH exchanges withD₂O); 6.68 (d, 1H, J=3.8 Hz); 6.83 (d, 1H, J=3.8 Hz); 6.90-6.98 (m, 3H);7.20-7.30 (m, 2H); 7.37-7.38 (m; 2H); 7.53 (s, 1H); 8.56 (d, 1H, NHexchanges with D₂O); ¹³C-NMR (CDCl₃) δ 9.49 (CH₃); 113.61 (CH x2);119.54 (C); 121.20 (CH); 126.46 (CH); 127.30 (C); 128.03 (CH); 128.32(CH); 129.17 (CH x2); 130.39 (CH); 130.63 (CH); 132.67 (C); 133.66 (C);135.51 (C); 136.68 (C); 137.18 (C); 143.16 (C); 148.16 (C); 162.39 (CO);Anal. calc. for C₂₁H₁₅Cl₃N₄OS: C, 52.79; H, 3.16; Cl, 22.26; N, 11.73.Found: C, 52.71; H, 3.16; Cl, 22.23; N, 11.75.

Example 3.1g Preparation of the ester-amide adduct of the 1-(5-Chloropentyl)-5-(5′-chloro-thiophen-2-yl)-4-methyl-1H-pyrazol-3-carboxylicacid

To a suspension of the acid obtained in the Example 2.2 (0.64 mmol, 1eq) in dichloromethane (1.3 ml), HOBt (1-hydroxybenzothiazole 0.77 mmol,1.2 eq) and EDC (0.77 mmol, 1.2 eq) were added. The solution was stirredat room temperature for 30 min, then used as such for preparing thecompound described in the Example 3.1 h.

Example 3.1h Preparation ofN-Piperidinyl-1-(5-chloropentyl)-5-(5′-chloro-thiophen-2′-yl)-4-methyl-1H-pyrazol-3-carboxamide

The solution of the compound prepared in the Example 3.1g was added, byquick dripping, to a solution of 1-aminopiperidine (1.28 mmol, 2 eq) indichloromethane (2 ml). The reaction mixture was stirred at roomtemperature for 30 min. After having removed the solvent, the obtainedproduct was purified by flash chromatography (oil ether/ethyl acetate8/2) obtaining a yellow oil which was treated with oil ether to obtainthe expected product as a white solid (23% yield). Rf 0.16 (oilether/ethyl acetate 7/3); m.p.: 72-73° C.; IR (nujol) (λ=cm⁻¹) 1662(C═O); 3217 (NH); ¹H-NMR (CDCl₃) δ 1.37-1.56 (m, 4H); 1.71-1.82 (m, 8H);2.27 (s, 3H); 2.88 (t, 4H, J=5.8 Hz); 3.51 (t, 2H, J=6.4 Hz); 4.06 (t,2H, J=7.2 Hz); 6.81 (d, 1H, J=3.8 Hz); 6.98 (d, 1H, J=3.6 Hz); 7.59 (s,1H, NH exchanges with D₂O); ¹³C-NMR (CDCl₃) δ 9.26 (CH₃); 23.39 (CH₂);23.78 (CH₂); 25.47 (2×CH₂); 29.56 (CH₂); 31.85 (CH₂); 44.63 (CH₂).;49.78 (CH₂); 57.11 (2×CH₂); 120.11 (C); 126.70 (CH); 127.78 (C); 129.02(CH); 132.56 (C); 134.63 (C); 141.83 (C) 160.15 (CO); Anal. calc. forCl₉H₂₆Cl₂N₄OS: C, 53.14; H, 6.10; Cl, 16.51; N, 13.05; S, 7.47. Found:C, 52.98; H, 6.08; Cl, 16.55; N, 13.08; S, 7.48.

Examples of other compounds of formula (I) are described in Table 1. Thestarting acids used are those of the Examples 2.1 and 2.2; the syntheseswere carried out analogously to what described in the Examples3.1a-3.1h., by using reactants known in the prior art.

TABLE 1 (I)

Yield m.p. Empirical IR Ex. B T′ (%) (° C.) Formula (λ = cm⁻¹) ¹H-NMR (δppm) 3.1i CH₃

78.26 58-62 C₂₅H₂₆Cl₃N₃OS 3423 (NH), 1676 (C═O); 0.82-0.94 (m, 2H); 1.07(s, 3H); 1.19 (s, 3H); 1.45-1.62 (m, 1H); 1.82-2.04 (m, 4H); 2.21-2.43(m, 2H); 2.47 (s, 3H); 3.26-3.57 (m, 2H); 6.65 (d, 1H, J = 3.6 Hz); 6.81(d, 1H, J = 3.4 Hz); 6.94 (t, 1H); 7.31-7.39 (m, 2H); 7.51 (s, 1H); 3.1lCH₂CH₃

57.85 152-153 C₂₁H₂₁Cl₃N₄OS 3162 (NH), 1650 (C═O); 1.25 (t, 3H, J = 7.2Hz); 1.35-1.51 (m, 2H); 1.65-1.83 (m, 4H); 2.77-2.97 (m, 6H); 6.64 (d,1H, J = 3.8 Hz); 6.80 (d, 1H, J = 3.8 Hz); 7.32-7.39 (m, 2H); 7.50 (s,1H); 7.62 (br s, 1H, NH exchanges with D₂O); 3.1m CH₂CH₃

56.22 84-85 C₂₂H₂₃Cl₃N₄OS 3167 (NH), 1653 (C═O); 1.25 (t, 3H, J = 7.4Hz); 1.54-1.83 (m, 8H); 2.87 (q, 2H, J = 7.6 Hz); 3.14 (t, 4H, J = 4.8Hz); 6.63 (d, 1H, J = 4.0 Hz); 6.80 (d, 1H, J = 3.6 Hz); 7.31-7.39 (m,2H); 7.49 (s, 1H); 8.02 (br s, 1H, NH exch. with D₂O); 3.1n CH₂CH₃

63.83 134-135 C₂₀H₁₉Cl₃N₄OS 3233 (NH), 1667 (C═O); 1.25 (t, 3H, J = 7.6Hz); 1.86-1.93 (m, 4H); 2.88 (q, 2H, J = 7.2 Hz); 2.95-3.05 (m, 4H);6.64 (d, 1H, J = 4.0 Hz); 6.80 (d, 1H, J = 4.0 Hz); 7.33-7.35 (m, 2H);7.49 (s, 1H); 7.59 (br s, 1H, NH exchanges with D₂O); 3.1o CH₂CH₃

54.62 194-195 C₂₂H₁₆Cl₃N₃OS 3381 (NH), 1675 (C═O); 1.29 (t, 3H, J = 7.4Hz); 2.94 (q, 2H J = 7.6 Hz); 6.68 (d, 1H, J = 3.8 Hz); 6.83 (d, 1H, J =4.0 Hz); 7.11 (t, 1H, J = 7.6 Hz); 7.31-7.38 (m, 4H); 7.52 (s, 1H); 7.68(d, 2H, J = 8.8 Hz); 8.77 (br s, 1H, NH exchanges with D₂O); 3.1p CH₂CH₃

60.98 58-62 C₂₂H₁₇Cl₃N₄OS 3416 (NH), 3283 (NH), 1681 (C═O); 1.22 (t, 3H,J = 7.4 Hz); 2.85 (q, 2H J = 7.2 Hz); 6.20 (br s, 1H, NH exch. withD₂O); 6.66 (d, 1H, J = 4.0 Hz); 6.82 (d, 1H, J = 4.0 Hz); 6.90-6.97 (m,3H); 7.20-7.28 (m, 2H); 7.36-7.37 (m, 2H); 7.52 (s, 1H); 8.56 (br s, 1H,NH exchanges with D₂O); 3.1q CH₃ —(CH₂)₄—CH₃ 24 887-88  C₂₀H₂₀Cl₃N₃OS3420 0.82-0.95 (m, 3H); 1.26-1.39 (m, 4H); (NH), 1.51-1.63 (m, 2H); 2.471721 (s, 3H); 3.40 (q, 2H, J = (C═O); 6.6 Hz); 6.66 (d, 1H, J = 4.0 Hz);6.81 (d, 1H, J = 3.6 Hz); 6.93 (br s, 1H, NH exchanges with D₂O);7.32-7.37 (m, 2H); 7.48-7.53 (m, 1H); 3.1r CH₂CH₃

78.36 52-54 C₂₆H₂₈Cl₃N₃OS 3424 (NH), 1681 (C═O); 0.87 (s, 1H); 0.92 (s,1H); 1.07 (s, 3H); 1.19 (s, 3H); 1.25 (t, 3H); 1.51-1.62 (m, 1H);1.82-2.02 (m, 4H); 2.22-2.40 (m, 2H); 2.89 (q, 2H); 3.31-3.54 (m, 2H);6.64 (d, 1H, J = 3.8 Hz); 6.80 (d, 1H, J = 3.4 Hz); 6.95 (t, 1H, NHexchanges with D₂O); 7.32-7.35 (m, 2H); 7.51 (s, 1H)

Example 4 Affinity Towards the Cannabinoidergic CB1 and CB2 Receptors

The affinity of the compounds of the present invention towards thecannabinoidergic CB1 and CB2 receptors was evaluated in vitro throughradioreceptorial binding studies by utilizing the method reported below.

The receptorial binding technique allows indeed to establish if and withwhat affinity and specificity a determined compound binds itself to aparticular receptor. To evaluate the affinity of a determined compoundtowards a particular receptor, a particular preparation of the tissuewherein the receptors are present is used and the tested compound ismade to compete with another compound, treated so as to make itradioactive and of which the affinity for the receptor is known. Thecapability of the tested compound to remove the radioactive compoundgives an index of the affinity by which the compound binds itself tothat determined receptor. The reading of the radioactivity present inthe receptor-compound complex allows furthermore to precisely calculatethe compound amount bound to the receptor. By this method it istherefore possible to rapidely identify the affinity of a new compoundtowards a specific receptor and thus to make predictions on itspharmacological activity. By repeating the same experimental scheme itis possible to evaluate the affinity of the compound towards other kindsof receptors and thus establish the specificity degree.

The receptorial binding technique, besides being used for the screeningof new molecules having a pharmacological activity, can give usefulinformation on possible changes at a receptorial level correlated forexample to a prolonged exposure to drugs and/or to particularpathologies. As a matter of fact, in these situations, changes in theamount of the receptors present or structural changes can be pointed outwhich alter the agonist or antagonist affinity and consequentlyinfluence the normal function of the receptors themselves.

The experimentation was carried out according to the guide lines of theEuropean Community for the animal experimentation (EEC No. 86/609), byemploying laboratory animals (rats) housed in groups of twenty for cage,under standard stalling conditions (temperature 22±2° C., relativehumidity 60%, artificial lighting with a 12 hour light-dark cycle). Foodand water were available ad libitum.

The procedure used, based on the employment of the compound[³H]-CP-55,940 (New England Nuclear, Boston, Mass., USA), implies theutilization of rat brain as biological tissue for the evaluation of theaffinity towards the CB1 receptors and of rat spleen for the affinitydetermination towards the CB2 receptors.

The animals were sacrificed by cervical dislocation, the brain in toto(cerebellum excluded) and the spleen were rapidely dissected andmaintained in ice.

The tissue was homogenized in 15 volumes (weight/volume) of TME buffer(50 mM Tris, 1 mM EDTA e 3 mM MgCl₂, pH 7.4) by an Ultra-Turrax andcentrifuged for 10 minutes at 1086×g in a centrifuge cooled at 4° C. Theresulting supernatant was centrifuged at 45,000×g for 30 min at 4° C. byusing a Beckman SW41 rotor and the final pellet was resuspended in 50volumes of TME.

The obtained membranes (50-80 μg of proteins) were incubated in thepresence of 1 nM di [³H]-CP55,940 for 1 h at 30° C. in a final volume of0.5 ml of TME buffer containing 5 mg/ml of bovine serum albumin (BSA).The non specific binding was measured in the presence of CP55,940 at the1 μM concentration. All the experiments were carried out inpolypropylene test tubes pretreated with Sigma-Cote (Sigma Chemical Co.Ltd., Poole, UK) to reduce the non specific binding.

For the building of the competitive inhibition binding curves eightdifferent concentrations of each compound were used. As referencecompounds SR141716A for the CB1 receptors and SR144528 for the CB2receptors were utilized.

Incubation was interrupted by addition of TME buffer (at 4° C.)containing 5 mg/ml of BSA and filtration under vacuum through WhatmanGFC filters pretreated with 0.5% of polyethylamine (PEI) and by using afiltering apparatus (Brandell, Gaithersburg, Md., USA). Filters werewashed 3 times with 5 ml of This HCl buffer (pH 7.4, 4° C.) containing 1mg/ml of BSA and singly placed in plastic vials containing 4 ml ofliquid for scintigraphy (Ultima Gold MV, Packard).

The radioactivity present in the filters was measured by a scintillatorspectrophotometer (Tricarb 2100, Packard, Meridien, USA).

The protein determination was carried out by the Bradford method byusing the protocol and the reactants supplied by Bio-Rad (Milano,Italia).

The experiments were carried out in triplicate and the results confirmedin five independent experiments.

The affinity of the compounds towards the CB1 and CB2 receptors wasexpressed in Ki terms.

Table 4 shows the Ki values obtained with the compounds of the presentinvention, examined in the test in vitro. The affinity of the compoundsof the present invention is compared with that relating to the referencecompounds SR144528 and SR141716A (Rimonobant®),

The Table shows that the compounds of the present invention haveactivity on the CB1 and/or CB2 receptors comparable with that of theprior art compounds active on said receptors.

Example 5 Hypothermia Tests In vivo

As said, the compounds having cannabimimetic activity show in vivo thefollowing effects: hypoactivity, hypothermia, analgesia and catalepsy(B. R. Martin et al., Pharmacol. Biochem. Behav.; 1991, 40, 471-478; P.B. Smith et al.; J. Pharmacol. Exp. Ther.; 1994, 270, 219-227). To beable to exert the thermoregulation function, the compounds havingactivity towards the cannabinoidergic receptors must be capable to passthe hemato-encephalic barrier, the central site of said receptorsregulating the temperature being positioned in the preoptical frontnucleus of the hypothalamus (S. M. Rawls et al.; J. Pharmacol. Exp.Ther.; 2002, 303, 395-402). Following treatments with CB1 agonistcompounds capable to pass the hemato-encephalic barrier, thecannabimimetic activity pointed out itself by the registration of areduction of the body temperature. In the case of CB1 antagonistcompounds capable to pass the hemato-encephalic barrier, the treatmentwith said compounds does not imply any body temperature variation,however it implies an antagonist activity towards reference CB1 agonistsas WIN 55,212-2, thus contrasting the hypothermia induced by the latter.

To evaluate the activity in vivo of the compounds of general formula(I), tests were therefore carried out to evaluate the hypothermiainduced as a result of treatments carried out with said compounds. Testswere carried out in the experiment animal (rat) according to the workindications by M. Rinaldi-Carmona et al. in FEBS Letters; 1994, 350,240-244. The rectal temperature in the rat was determined by anelectronic thermometer inserted at a 2 mm depth. The measurements werecarried out on rats acclimated for one hour. The rectal temperature wasdetermined before and after (from 30 to 120 minutes) the i.p.administration of the compound to be tested.

When no temperature reduction following the administration of thecompound to be tested was pointed out, it was evaluated the antagonistactivity of the same towards a reference CB1 agonist compound as WIN55,212-2. For this purpose the rectal temperature measurements werecarried out upon i.p. administration of the compound to be tested 30minutes before the WIN 55,212-2 administration. The compounds capable topass the hemato-encephalic barrier and to antagonise the CB1 agonistactivity of WIN 55,212-2 are indeed capable to contrast the temperaturereduction induced by the reference agonist.

Each test was repeated on ten animals; the reported results are theaverage of the results obtained with the ten animals.

The Examples reported hereinafter show that the invention compounds (I)(Examples 5.1 and 5.2), having affinity towards the CB1 receptors as ithas been shown in the tests in vitro of the Examples 4, are able to passthe hematoencephalic barrier. In particular the compounds of formula (I)of the Examples 5.1 and 5.2, not having as such any effect on the bodytemperature, but being able to contrast the temperature reductioninduced by WIN 55,212-2, are CB1 antagonists.

Example 5.1

The test was carried out with the compound of the Example 3.1c. Aqueoussamples were used wherein the compound of the Example 3.1c was dispersedin water with three drops of Tween 80. Following the above procedure,treatments were carried out with doses (mg compound/kg of body weight)respectively of 0.1; 0.5; 1.0; 3.0; 6.0.

In none of the examined cases there was a reduction of the bodytemperature in the treated rats with respect to the physiologicalsolution administration (38° C.).

In the case of the evaluation of the antagonist activity towards WIN55,212-2 (3 mg compound/kg of body weight), substantial variations ofthe body temperature were instead pointed out with respect to thetreatment with the only WIN 55,212-2. In particular the compound of theExample 3.1b was able to antagonize the effect of WIN 55,212-2 (Calagonist), contrasting the effect of the reduction of the bodytemperature induced by the CB1 agonist administration.

The compound of the Example 3.1b is thus capable to pass thehemato-encephalic barrier and, shows a CB1 antagonist behaviour.

The temperatures detected during the experiment, from the zero time(i.p. administration of the CB1 agonist WIN 55,212-2)) up to 120 min arereported in Table 5.

Example 5.2

The Example 5.1 was repeated but with the compound of the Example 3.1dinstead of that of the Example 3.1b.

As in case of the compound of the Example 3.1b, also the compound of theExample 3.1d does not cause as such any effect on the body temperature.Said compound is able to pass the hemato-encephalic barrier antagonizingthe effect of the CB1 agonist WIN 55,212-2.

With none of the doses employed a reduction of the body temperature inthe treated rats was indeed noticed. In the case of the evaluation ofthe antagonist activity towards WIN 55,212-2 (3 mg compound/kg of bodyweight), substantial variations of the body temperature were insteadpointed out with respect to the treatment with the only WIN 55,212-2. Inparticular the compound of the Example 3.1d was able to antagonize theeffect of WIN 55,212-2 (CB1 agonist), contrasting the effect of thereduction of the body temperature induced by the CB1 agonistadministration.

The temperatures detected during the experiment, from zero time (i.p.administration of the CB1 agonist WIN 55,212-2) up to 120 min arereported in Table 6.

Example 6 Intestinal Motility Tests

To further evaluate the activity in vivo of the compounds (I) object ofthe present invention, functional tests were carried out to evaluate theeffect of said compounds on the rat intestinal motility. It was indeedshown the involvement of the cannabinoidergic CB1 receptors in theintestinal motility regulation in rat (R. G. Pertwee et al; Br. J.Pharmacol.; 1996, 118, 2199-2205). In particular, the CB1 receptoragonists slacken the gastrointestinal motility; antagonist compounds ofthe same receptors have instead a prokinetic effect on thegastrointestinal transit (G. Colombo et al.; Eur. J. Pharmacol.; 1998,344, 67-69; M. A. Casu et al.; Eur. J. Pharmacol.; 2003, 459, 97-105).

The evaluation of the constipating or prokinetic effect of the compoundswas carried out by the Upper Gut Transit Test method on the basis of theprocedure defined and ratified by Y. Nagakura et al.; Eur. J.Pharmacol.; 1996, 311, 67-72. The method, which allows to measure themotility of the stomach and of the first intestine tract (small orlittle intestine), implies:

-   -   the administration of the compound to be tested by i.p. route;    -   the administration of carmine red (marker not directly        absorbable from the stomach) by intragastric route through a        metal probe, after 20 minutes from the administration of the        compound to be tested;    -   the rat sacrifice by cervical dislocation after a pre-fixed time        (30 minutes) starting from the administration time;    -   the intestine explant from pylorus to the ileo-cecal valve;    -   the determination of the intestinal part crossed by the marker;    -   the data processing to determine the percentage of crossed part        with respect to the total length of the small intestine.

With respect to the control (physiological solution or carrier whereinthe compounds to be tested were solubilized or dispersed), theadministration of CB1 agonist compounds implies a reduction of theintestinal transit percentage; an opposite effect is noticed in case ofantagonist compounds. The latter are therefore capable to cancel theconstipating effect of CB1 agonist compounds.

Each test was repeated on ten animals; the results reported in theExamples are the average of the results obtained with ten animals.

The Examples reported hereinafter show that the invention compounds (I)are active on the gastrointestinal tract. In particular the compounds ofthe Examples 3.1b and 3.1d increase the intestinal transit rate and arecapable to antagonize the effect of a CB1 agonist as the compound WIN55,212-2, implying a prokinetic effect on the gastrointestinal tract.

Example 6.1

The test was carried out with the compound of the Example 3.1b; aqueoussamples were in particular used wherein the compound 3.1b was dispersedin water with three drops of Tween 80. According to the above procedure,with treatments respectively equal to 0.5 and 1.0 mg of compound/kg ofbody weight, the marker has run on an average an intestinal portionequal to, respectively, 1.57 and 1.76 times the length run from themarker in the intestine following the administration of a physiologicalsolution containing the same amount of Tween 80.

The prokinetic effect of the compound of the Example 3.1b was evaluatedalso towards the constipating action of the CB1 agonist compound WIN55,212-2. The treatment of rats with aqueous samples of WIN 55,212-2with concentrations equal to 0.5 mg of compound/kg of body weight, hasimplied a covering of the intestinal transit from the marker equal to0.16 times the length run from the marker in the intestine following theadministration of a physiological solution containing the same aboveindicated amount of Tween 80. In the case of similar treatment with WIN55,212-2 preceded by the administration of an aqueous sample of thecompound of the Example 3.1b with concentration equal to 1.0 mg ofcompound/kg of body weight, the marker has instead run, on, an average,the same length run in the intestine following the administration of aphysiological solution containing the same amount of Tween 80. Thecompound of the Example 3.1b, under the above conditions, was thereforecapable to antagonize the constipating effect of the CB1 agonist WIN55,212-2.

Example 6.2

The Example 6.1 was repeated but by using the compound of formula (I) ofthe Example 3.1d at the place of the compound of the Example 3.1b. Withtreatments respectively equal to 0.5 and 1.0 mg of compound/kg of bodyweight, the marker has run on an average an intestinal portionrespectively equal to 1.61 and to 1.74 times the length run by themarker in the intestine following the administration of a physiologicalsolution containing the same amount of Tween 80.

In this case also the prokinetic effect of the compound of the Example3.1d was evaluated towards the constipating action of the CB1 agonistcompound WIN 55,212-2. The rat treatment with aqueous samples of WIN55,212-2 with concentrations equal to 0.5 mg of compound/kg of bodyweight, has implied a covering of the intestinal transit from the markerequal to 0.16 times the length covered by the marker in the intestinefollowing the administration of a physiological solution containing thesame above indicated amount of Tween 80. In case of similar treatmentwith WIN 55,212-2 preceded by the administration of an aqueous sample ofthe compound of the Example 3.1d with concentration equal to 0.5 mg ofcompound/kg of body weight, the marker has instead run on an average thesame length run in the intestine following the administration of aphysiological solution containing the same amount of Tween 80. Thecompound of the Example 3.1d was thus able, under the above conditions,to antagonize the constipating effect of the CB1 agonist WIN 55,212-2.

TABLE 4 Example 4: activity in vitro of the invention compounds on theCB1 and CB2 receptors, compared with that of the reference compoundsSR144528 and SR141716A Compound CB1 (brain) CB2 (spleen) (Ex.) Ki (nM)Ki (nM) 3.1b 35.0 ± 2.5 476.0 ± 3.0  3.1c 21.0 ± 1.0 270.0 ± 5.0  3.1d63.0 ± 7.2 699.0 ± 21.0 SR144528 (comp)  70 ± 10  0.28 ± 0.04SR141716A(comp)   1.8 ± 0.075 514 ± 30

TABLE 5 Pharmacological Example 5.1: trend of the body temperature afteradministration in rat (10 animals) of WIN 55,212-2 as such or incombination with the compound of the Example 3.1b in the doses indicatedin the Table. The average animal body temperature after administrationof a physiological solution is 38° C. Time from the Body temperature (°C.) administration WIN WIN 55,212-2 (3 mg/kg) + compound of WIN 55,212-255,212-2 Ex. 3.1b (conc in mg/kg) (minutes) (3 mg/kg) 0.1 0.5 1.0 3.06.0 0 37.9 38.5 38.1 38.3 38.4 38.6 15 35.6 35.1 35.8 36.1 36.1 37.7 3033.8 33.8 34.5 35.7 35.7 37.9 60 34.5 35.3 35.7 36.8 36.8 37.9 90 35.836.9 36.7 37.8 37.8 38.2 120 36.8 37.3 37.3 37.9 37.9 37.9

TABLE 6 Pharmacological Example 5.2: trend of the body temperature afteradministration in rat (10 animals) of WIN 55,212-2 as such or incombination with the compound of the Example 3.1d in the doses indicatedin the Table. The body temperature after administration of aphysiological solution is 38° C. Time from the Body temperature (° C.)administration WIN WIN 55,212-2 (3 mg/kg) + compund of WIN 55,212-255,212-2 Ex. 3.1d (conc. in mg/kg) (minutes) (3 mg/kg) 0.1 0.5 1.0 3.06.0 0 37.9 38.1 38.1 37.9 38.4 37.8 15 35.6 35.3 35.7 36.5 37.0 36.9 3033.8 33.8 34.4 34.7 36.8 36.9 60 34.5 35.6 35.0 35.8 37.3 37.2 90 35.836.5 36.3 36.7 37.7 37.8 120 36.8 37.2 37.2 37.1 37.6 37.9

1. A method a treating disease comprising administering to a patient inneed thereof a pharmaceutically acceptable amount of a compound ofFormula (I)

wherein R is aryl, not substituted or having from one to fivesubstituents, equal to or different from each other, selected fromhalogen, C₁-C₇ alkyl, C₁-C₇ alkylthio, C₁-C₇ alkoxy, C₁-C₇ haloalkyl,C₁-C₇ haloalkoxy, cyano, nitro, amino, N-alkylamino, N,N-dialkylamino,saturated or unsaturated heterocycle, and phenyl; A is an amidicsubstituent of formula —C(O)—NH-T, wherein T is a group NR₁R₂, whereinR₁ and R₂ are equal or different and have the following meanings: C₁-C₇alkyl; aryl, arylalkyl or arylalkenyl not substituted or optionallyhaving on the aromatic rings from one to four substituents, equal to ordifferent from each other, selected from halogen, C₁-C₇ alkyl, C₁-C₇haloalkyl, C₁-C₇ haloalkoxy, C₁-C₇ alkylthio, C₁-C₇ alkoxy, wherein inthe previous substituents comprising C₁-C₇ aliphatic chains, C₁-C₃chains are preferably used; wherein R₁ may additionally be hydrogen; orR₁ and R₂ together with the nitrogen atom to which they are linked forma, saturated or unsaturated, heterocycle from 5 to 10 atoms comprisingcarbon atoms and including the nitrogen of NR₁R₂, and optionally anadditional S, O or N atom, not substituted or optionally having from oneto four substituents, equal to or different from each other, selectedfrom C₁-C₇ alkyl, phenyl, and benzyl, said phenyl or benzyl optionallysubstituted with one or more groups, equal to or different from eachother, selected from: halogen, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇haloalkoxy, C₁-C₇ alkylthio and C₁-C₇ alkoxy; B is a group selectedfrom: hydrogen and C₁-C₄ alkyl; and D is an heteroaryl with a ring sizeof from 5 to 6 atoms, selected from the group consisting of thiophene,pyridine, furan, oxazole, thiazole, imidazole, pyrazole, isoxazole,isothiazole, triazole, pyridazine, pyrimidine, pyrazine, triazine andpyrrole; wherein the heteroaryl is optionally substituted with one, two,three or four substituents, equal to or different from each other,selected from the following: halogen, C₁-C₃ alkyl, C₁-C₃ alkylthio,C₁-C₃ alkoxy, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, wherein the compound ofFormula (I) exhibits an affinity for CB1 receptors, and wherein thedisease is selected from the group consisting of inflammation,schizophrenia, depression, hemicrania, stress, epilepsy, Tourettesyndrome, Parkinson disease, Huntington disease, Alzheimer disease, andsenile dementia.
 2. The method of claim 1, wherein the compounds areradiomarked for the identification and marking of cannabinoidertic CB1receptors.
 3. A method a treating disease comprising administering to apatient in need thereof a pharmaceutically acceptable amount of acompound of Formula (I)

wherein R is aryl, not substituted or having from one to fivesubstituents, equal to or different from each other, selected fromhalogen, C₁-C₇ alkyl, C₁-C₇ alkylthio, C₁-C₇ alkoxy, C₁-C₇ haloalkyl,C₁-C₇ haloalkoxy, cyano, nitro, amino, N-alkylamino, N,N-dialkylamino,saturated or unsaturated heterocycle, and phenyl; A is an amidicsubstituent of formula —C(O)—NH-T, wherein T is a group NR₁R₂, whereinR₁ and R₂ are equal or different and have the following meanings: C₁-C₇alkyl; aryl, arylalkyl or arylalkenyl not substituted or optionallyhaving on the aromatic rings from one to four substituents, equal to ordifferent from each other, selected from halogen, C₁-C₇ alkyl, C₁-C₇haloalkyl, C₁-C₇ haloalkoxy, C₁-C₇ alkylthio, C₁-C₇ alkoxy, wherein inthe previous substituents comprising C₁-C₇ aliphatic chains, C₁-C₃chains are preferably used; wherein R₁ may additionally be hydrogen; orR₁ and R₂ together with the nitrogen atom to which they are linked forma, saturated or unsaturated, heterocycle from 5 to 10 atoms comprisingcarbon atoms and including the nitrogen of NR₁R₂, and optionally anadditional S, O or N atom, not substituted or optionally having from oneto four substituents, equal to or different from each other, selectedfrom C₁-C₇ alkyl, phenyl, and benzyl, said phenyl or benzyl optionallysubstituted with one or more groups, equal to or different from eachother, selected from: halogen, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇haloalkoxy, C₁-C₇ alkylthio and C₁-C₇ alkoxy; B is a group selectedfrom: hydrogen and C₁-C₄ alkyl; and D is an heteroaryl with a ring sizeof from 5 to 6 atoms, selected from the group consisting of thiophene,pyridine, furan, oxazole, thiazole, imidazole, pyrazole, isoxazole,isothiazole, triazole, pyridazine, pyrimidine, pyrazine, triazine andpyrrole; wherein the heteroaryl is optionally substituted with one, two,three or four substituents, equal to or different from each other,selected from the following: halogen, C₁-C₃ alkyl, C₁-C₃ alkylthio,C₁-C₃ alkoxy, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, wherein the compound ofFormula (I) exhibits an affinity for CB2 receptors, and wherein thedisease is selected from the group consisting osteoporosis, renalischemia, GVHD (Graft Versus Host Disease), erythematous systemic lupus,ankylosing spondylitis, polyarthritis, rheumatoid arthritis, hemolyticautoimmune anemia, Behcet disease, Sjögren syndrome, undifferentiatedspondylarthritis, reactive arthritis, and dermatomyositis.
 4. The methodof claim 3, wherein the compounds are radiomarked for the identificationand marking of cannabinoidertic CB2 receptors.